Quinidine

Quinidine is an antiarrhythmic Class 1 A agent belonging to a Sodium channel blocker.

Quinidine is a sodium channel blocker used in the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Quinidine is used in the treatment of atrial fibrillation and flutter, ventricular arrhythmias and to restore normal sinus rhythm. It is also used in the treatment of Malaria, Brugada syndrome, and short QT syndrome.

The common side effects are GI irritation (e.g. nausea, vomiting, diarrhea, oesophagitis, abdominal pain), resp difficulties, pruritus, urticaria, rash, thrombocytopenic purpura, blood dyscrasias, granulomatous hepatitis, lupus-like syndrome, etc.

Quinidine is available in the form of a dosage form such as Tablets, injection

Quinidine is available in Switzerland, Europe, India, Japan, U.S

Quinidine has a complex electrophysiological profile that has not been fully elucidated. The antiarrhythmic actions of this drug are mediated through effects on sodium channels in Purkinje fibers. Quinidine blocks the rapid sodium channel (INa), decreasing the phase zero of rapid depolarization of the action potential.

Quinidine also reduces repolarizing K+ currents (IKr, IKs), the inward rectifier potassium current (IK1), and the transient outward potassium current Ito, as well as the L-type calcium current ICa and the late INa inward current. The reduction of these currents leads to the prolongation of the action's potential duration. By shortening the plateau but prolonging late depolarization, quinidine facilitates the formation of early after depolarisation (EAD).

Additionally, in patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide and is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum.

The Duration of Action of Quinidine was within 6-8 hrs

The Tmax was about 6-8 hr and Cmax was about 9 h, respectively

Quinidine is available in the form of Tablets.

Quinidine is used in the treatment of atrial fibrillation and flutter, ventricular arrhythmias and to restore normal sinus rhythm. It is also used in the treatment of Malaria, Brugada syndrome, and short QT syndrome.

It prolongs cellular action potential by blocking sodium and potassium currents. It continues to be used in the treatment of Malaria, Brugada syndrome, short QT syndrome, and idiopathic ventricular fibrillation

Quinidine is used in the treatment of atrial fibrillation and flutter, ventricular arrhythmias and to restore normal sinus rhythm. It is also used in the treatment of Brugada syndrome and short QT syndrome.

• Conversion of Atrial Fibrillation/Flutter to Sinus Rhythm

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine sulfate only after ventricular rate control (e.g., with digitalis or β-blockers) has failed to provide satisfactory control of symptoms. Adequate trials have not identified an optimal regimen of quinidine sulfate for conversion of atrial fibrillation/flutter to sinus rhythm.

Dosing Information

Therapy with quinidine sulfate should begin with one tablet (300 mg; 249 mg of quinidine base) every 8 to 12 hours.

If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if this regimen has not resulted in conversion, then the dose may be cautiously raised. If at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QTc interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine sulfate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered.

• Reduction of Frequency of Relapse into Atrial Fibrillation/Flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine sulfate should be an increase in the average time between episodes. In most patients, tachyarrhythmia will recur during therapy with quinidine sulfate, and a single recurrence should not be interpreted as therapeutic failure.

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged.

Dosing Information

Therapy with quinidine sulfate should begin with one tablet (300 mg; 249 mg of quinidine base) every eight to twelve hours.

If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QTc interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension.

• Suppression of Ventricular Arrhythmias

Dosing regimens for the use of quinidine sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

Although not approved there have been certain off-label use documented for Quinidine which includes:-

• Malaria

Regimen I

Load: 24 mg/kg diluted in 250 mL NS IV infusion over 4 hours

Maintenance: Follow by 12 mg/kg IV infusion over 4 hours at every 8 hours beginning 8 hr after initiation of loading dose except in patients able to swallow the same doses of quinidine are administered using 300 mg quinidine sulfate tablets

Regimen II

Load: 10 mg/kg diluted in 5 mL/kg NS IV over 1-2 hr

Maintenance: Follow by 0.02 mg/kg/min continuous IV infusion; in patients able to swallow oral quinine is administered every 8 hr to give as much quinine as the patient received quinidine every 8 hours.

PO regimen: 300 mg quinidine or 650 mg quinine taken orally every 8 hours for 3 days (Africa and South America) or 7 days (Southeast Asia) or until parasitemia is reduced to 1%

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Quinidine is available in various dosage strengths of 80mg/mL, 200 mg, 300 mg, 324 mg

Quinidine is available in the form of Tablets and injections.

Quinidine is a sodium channel blocker used in the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Primary hyperkalemic and hypokalemic periodic paralysis Food that is high in carbohydrates and low in potassium. Because muscle tissue is stressed in the periodic paralyzes it is also essential that patients obtain liberal amounts of high-quality protein.

The dietary restriction should be individualized as per the patient's requirements.

Quinidine may be contraindicated in the following

• Systemic mastocytosis
• Low amount of magnesium in the blood
• Low amount of potassium in the blood
• Decreased blood platelets
• Myasthenia gravis, a skeletal muscle disorder
• Complete heart block
• Partial heart block
• Torsades de pointes, a type of abnormal heart rhythm
• Prolonged qt interval on EKG
• Chronic heart failure.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Proarrhythmic Effects

Like many other drugs (including all other Class la antiarrhythmics), quinidine prolongs the QT c interval, and this can lead to torsades de pointes, a life-threatening ventricular arrhythmia. The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, or high serum levels of quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QT c interval, and quinidine should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT c interval. Estimation of the incidence of torsades in patients with therapeutic levels of quinidine is not possible from the available data, the resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of quinidine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a (beta)-receptor blocking agent.

• Exacerbated Bradycardia in Sick Sinus Syndrome

In patients with sick sinus syndrome, quinidine has been associated with marked sinus node depression and bradycardia.

Vagolysis

Because quinidine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine.

Precautions

• General

All the precautions applying to regular quinidine therapy apply to this product. Hypersensitivity or anaphylactoid reactions to quinidine, although rare, should be considered, especially during the first weeks of therapy. Hospitalization for close clinical observation, electrocardiographic monitoring, and determination of serum quinidine levels are indicated when large doses of quinidine are used or with patients who present an increased risk.

• Laboratory Tests

Periodic blood counts and liver and kidney function tests should be performed during long-term therapy; the drug should be discontinued if blood dyscrasias or evidence of hepatic or renal dysfunction occurs.

• Heart Block

In patients without implanted pacemakers who are at high risk of the complete atrioventricular block (e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.

Alcohol consumption with Quinidine may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Quinidine use in breastfeeding patients is not recommended.

Pregnancy Category X

Risk Summary

Quinidine may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.

Quinidine was teratogenic and embryotoxic in rats at doses with exposures to an unbound drug that was approximately 8 Times and 2 times, respectively, the human exposure. In rabbits, Quinidine led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Quinidine is used in pregnancy, or if the

If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Grapefruit juice during treatment with Quinidine unless specifically directed otherwise by your doctor. Grapefruit and grapefruit juice can interact with Quinidine and decrease the levels of Quinidine in your body.

The adverse reactions related to the molecule Quinidine can be categorized as

• Common Adverse effects:

GI irritation (e.g. nausea, vomiting, diarrhea, oesophagitis, abdominal pain), resp difficulties, pruritus, urticaria, rash, thrombocytopenic purpura, blood dyscrasias, granulomatous hepatitis, lupus-like syndrome.

• Less Common adverse effects:

Cinchonism w/ tinnitus, impaired hearing, visual disturbances, confusion, vertigo, headache, delirium; syncope.

• Rare adverse effects:

Anaphylaxis, fever.

The clinically relevant drug interactions of Quinidine are briefly summarized here.

• Decreased serum concentration with antacids, PPI, and CYP3A4 inducers (e.g., phenytoin, rifampicin).
• Increased plasma concentration with CYP1A1 (e.g. erlotinib), CYP3A4 inhibitors (e.g., clarithromycin), potent P-GP/BCRP inhibitors (e.g. ciclosporin, azole antifungals, protease inhibitors).
• Potentially Fatal: Enhanced hypotensive effect with amyl nitrate, nitroglycerin, and PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Resp to depression or distress, ataxia, apnoea, severe hypotension, syncope, diarrhea, vomiting, anuria, absence of P waves, PR and QT interval, and QRS complex broadening, extrasystoles, ventricular arrhythmias, heart block, heart failure, coma, irritability, lethargy, thrashing, hallucinations, twitching, paraesthesia, generalized seizures, signs of cinchonism.

Management:

Symptomatic treatment. Monitor ECG and BP. Perform gastric lavage, induce emesis, or administer activated charcoal for recent ingestion. May require artificial resp or other supportive measures.

Pharmacodynamics:

• Quinidine is an antimalarial schizonticide, and a class Ia antiarrhythmic agent used to interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, such as atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In most patients, quinidine can lead to an increase in the sinus rate. Quinidine also causes a marked prolongation of the QT interval in a dose-related manner, acts peripherally as an α-adrenergic antagonist, and has anticholinergic and negative inotropic activity.

Pharmacokinetics:

• Absorption:

The absolute bioavailability of quinidine sulfate is approximately 70%, but it ranges from 45% to 100%. The less-than-complete quinidine sulfate bioavailability is a result of first-pass metabolism in the liver.

• Distribution:

Quinidine has a volume of distribution of 2-3 L/kg in healthy young adults, 0.5 L/kg in patients with congestive heart failure, and 3-5 L/kg in patients with liver cirrhosis

• Metabolism:

Quinidine is mainly metabolized in the liver by cytochrome P450 enzymes, specifically CYP3A4. The major metabolite of quinidine is 3-hydroxy-quinidine, which has a volume of distribution larger than quinidine and an elimination half-life of about 12 hours.

• Excretion:

The elimination of quinidine is achieved by the renal excretion of the unchanged drug (15 to 40% of total clearance) and its hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance).

1. https://go.drugbank.com/drugs/DB00908
2. https://medlineplus.gov/druginfo/meds/a682396.html
3. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-new-risk-management-plan-and-patient-medication-guide-qualaquin